Compositions for achieving a therapeutic effect in an anatomical structure

ABSTRACT

Compositions and methods of using the compositions are provided for forming an embolus within a region of an anatomical lumen for a transitory period in order to achieve a therapeutic effect.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 14/074,201, filed on Nov. 7, 2013, published as U.S. PatentApplication Publication No. 2014-0065093 A1 on Mar. 6, 2014, andsubsequently issued as U.S. Pat. No. 9,011,928 on Apr. 21, 2015, whichis a divisional application of U.S. application Ser. No. 13/244,294,filed on Sep. 24, 2011, published on Feb. 9, 2012, as U.S. PatentApplication Publication No. 2012-0035107 A1, and subsequently issued asU.S. Pat. No. 8,632,820 B2 on Jan. 21, 2014, which is a continuation ofU.S. application Ser. No. 12/198,749 filed on Aug. 26, 2008, andsubsequently issued as U.S. Pat. No. 8,057,824 on Nov. 15, 2011, whichis a division of U.S. application Ser. No. 11/015,943 filed on Dec. 17,2004, and published as U.S. Pat App Pub No. 2005-0142202 A1 on Jun. 30,2005, which is a division of U.S. application Ser. No. 09/781,599 filedon Feb. 12, 2001, and subsequently issued as U.S. Pat. No. 7,008,642 onMar. 7, 2006; each of which is hereby incorporated by reference hereinin its entirety. Incorporation by reference of U.S. application Ser.Nos. 13/244,294 and 14/074,201 includes drawings.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to compositions that induce atherapeutic response within an anatomical structure. More specifically,the invention is directed to compositions of matter for achieving atherapeutic effect in a localized region of a mammalian lumen or networkof lumens, such as within the vascular system. Moreover, the inventionis directed to methods of using the compositions of matter for treatmentof the targeted area.

2. Description of the Related Art

The cardiovascular system is characterized by extensive branching ofblood vessels. The three major types of blood vessels are arteries,veins, and capillaries. Arteries and veins are distinguished by thedirection of blood flow within them rather than by the quality of theblood they carry. Most arteries, but not all, carry oxygenated blood,and most veins, but not all, carry deoxygenated blood. All arteriescarry blood from the heart to the capillaries, and all veins returnblood back to the heart from the capillaries. While arteries and veinsact as conduits for the flow of blood, capillaries come into intimatecontact with tissue cells to directly serve cellular needs. Exchange ofoxygen and carbon dioxide between the blood and tissue cells occursprimarily through the thin walls of the capillaries.

FIG. 1 illustrates the extensive branching of blood vessels in ananatomical structure 10 within the mammalian cardiovascular system. Asthe heart alternately contracts and relaxes, blood is forced in adirection 12 into successively smaller arterial vessels.

The three types of arterial vessels include elastic arteries 14,muscular arteries 16, and arterioles 18. Elastic arteries 14, such asthe aorta and major aortic branches, are the large, thick walledarteries near to the heart. Of the three types of arterial vessels,elastic arteries 14 are the largest in diameter and the most elastic.Elastic arteries 14 are sometimes referred to as conducting arteriesbecause the large diameters of the vessels provide little resistanceagainst the flow of blood. Muscular arteries 16, also referred to asdistributing arteries, are the second type of arterial vessel. Musculararteries 16 extend from elastic arteries 14 to deliver blood to specificorgans. The smallest of the arterial vessels are arterioles 18.Arterioles 18 typically have a lumen diameter smaller than 0.3 mm. Thesmallest arterioles 18 are little more than a single layer of smoothmuscle cells spiraling around the endothelial lining.

From arteriole 18, blood flows in direction 12 to capillaries 20.Capillaries 20 form networks of microscopic vessels that infiltratetissues. It is across the thin walls of capillaries 20 that bloodreleases oxygen and receives the carbon dioxide produced by cellularrespiration. The microscopic capillaries 20 are the smallest bloodvessels. In some cases, one cell forms the entire circumference of thecapillary wall.

Deoxygenated blood is carried in direction 12 from the bed ofcapillaries 20 toward the heart by venous vessels. En route, the venousvessels increase in diameter and their walls gradually thicken inprogression from venules 22 to small veins 24 to larger veins 26.Occlusion of venous vessels rarely blocks blood flow. The vast union ofbranches among the venous vessels provides alternative pathways for theflow of blood. Thus, if a region of a venous vessel becomes occluded,the anastomotic formation of the vessels allows for the propercirculation of blood back to the heart.

Occlusion of arterial vessels, however, typically reduces or blocksblood flow. During the course of atherosclerosis, for example, growthscalled plaques develop on the inner walls of the arteries and narrow thebore of the vessels. An embolis, or a moving clot, is more likely tobecome trapped in a vessel that has been narrowed by plaques. Further,plaques are common sites of thrombus formation. Together, these eventsincrease the risk of heart attacks and strokes.

Traditionally, critically stenosed atherosclerotic vessels have beentreated with bypass surgery in which veins removed from the legs, orsmall arteries removed from the thoracic cavity, are implanted in theaffected area to provide alternate routes of blood circulation. Morerecently, intravascular devices, such as stents, have been used to treatdiseased blood vessels.

Stents are scaffoldings, usually cylindrical or tubular in shape, whichfunction to physically hold open and, if desired, to expand the wall ofthe vessel. Typically stents are capable of being compressed, so thatthey may be inserted through small cavities via catheters, and thenexpanded to a larger diameter once they are at the desired location.

Although stents are significant innovations in the treatment of occludedvessels, a common problem with usage of stents is restenosis. Restenosisof the artery commonly develops over several months after a therapeuticprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. Restenosis is thought to involve the body's naturalhealing process. Angioplasty or other vascular procedures injure thevessel walls, removing the vascular endothelium, disturbing the tunicaintima, and causing the death of medial smooth muscle cells. Excessiveneoinitimal tissue formation, characterized by smooth muscle cellmigration and proliferation to the intima, follows the injury.Proliferation and migration of smooth muscle cells (SMC) from the medialayer to the intima cause an excessive production of extra cellularmatrices (ECM), which is believed to be one of the leading contributorsto the development of restenosis. The extensive thickening of thetissues narrows the lumen of the blood vessel, constricting or blockingblood flow through the vessel.

Thus, although stents are significant innovations in the treatment ofoccluded vessels, there remains a need for administering therapeuticsubstances to the treatment site. To provide an efficaciousconcentration to the treatment site, systemic administration of thetherapeutic substance often produces adverse or toxic side effects forthe patient. Local delivery is a highly suitable method of treatment, inthat smaller levels of therapeutic substances, as compared to systemicdosages, are concentrated at a specific site. Local delivery producesfewer side effects and achieves more effective results.

One commonly applied technique for the local delivery of a therapeuticsubstance employs a porous balloon attached to a distal end of acatheter assembly. The expansion of the balloon, which in effect resultsin the dilation of the occluded region, is accomplished by injecting atherapeutic substance into the balloon. The use of a therapeuticsubstance as an expansion fluid additionally functions as a medicamentfor the diseased region, as the therapeutic substance is discharged fromthe porous balloon during and subsequent to the expansion therapy. Ashortcoming associated with this procedure is that the therapeuticsubstance may be carried off in the patient's blood stream as it isbeing discharged from the balloon, which results in an ineffectivetreatment of the target site and adverse exposure of the substance tohealthy tissues.

Another technique for the local delivery of a therapeutic substanceemploys a medicated implantable device, such as a stent. A stent coatedwith a polymeric material, which is impregnated with a therapeuticsubstance, can be deployed at a selected site of treatment. Thepolymeric carrier allows for a sustained delivery of the therapeuticsubstance. An obstacle associated with the use of medicated stents isthe limited ability of the stents to access the smaller vessels withinthe mammalian cardiovascular system. Another obstacle associated withthe use of a medicated stent is that the therapeutic substance isprimarily delivered to the vessel wall which is in direct contact withthe stent. Thus, delivery of the therapeutic substance to otherlocalized areas of the vessel or to localized areas of tissue locatedadjacent to the vessel is not easily facilitated.

Another technique for the local delivery of a therapeutic substance isdisclosed in U.S. Pat. No. 5,879,713 to Roth et al. Roth et al. teachesthe administration of microparticles that include a polymeric carrierand biologically active molecules. The microparticles selectively lodgeat a targeted site within the vascular system for a sufficient amount oftime to permit controlled release of a therapeutically effective amountof the biologically active molecules. Roth et al. further teaches thatsuitable polymer compositions preferably have intrinsic and controllablebiodegradability, so that they persist for about a week to about sixmonths. A shortcoming of Roth et al., however, is that an embolizationperiod of one week may be too long for some vessels, such as those inthe brain or in the coronary system, and may thus lead to death in thetissue supplied by such vessels.

SUMMARY

In accordance with the present invention, a method of achieving atherapeutic effect is provided. The method includes providing a particlecontaining a therapeutic substance to an anatomical structure having alumen such that the particle embolizes within the lumen for a transitoryperiod of less than one week. The therapeutic substance is released fromthe particle, causing a therapeutic effect.

Another method of achieving a therapeutic effect is also provided. Themethod includes providing a particle to an anatomical structure having alumen such that the particle embolizes within the lumen for a transitoryperiod. The transitory period of embolization causes a brief period ofreduced blood flow through the lumen that induces a therapeutic bodilyresponse.

A composition for achieving a therapeutic effect in an anatomicalstructure having a lumen is also provided. The composition includes aparticle suitable for introduction into an anatomical structure. Theparticle contains a therapeutic substance and is capable of reducing insize. The particle is capable of embolizing within the lumen for atransitory period of less than one week. The therapeutic substance isreleased from the particle for the treatment of a patient.

Also provided is another composition for achieving a therapeutic effectin an anatomical structure having a lumen. The composition includes aparticle suitable for introduction into an anatomical structure andcapable of reducing in size. The particle is capable of embolizingwithin the lumen for a transitory period, causing a brief period ofreduced blood flow which induces a therapeutic bodily response.

Also provided is a method of achieving a therapeutic effect within ananatomical structure having a first region as well as a second regionlocated downstream of the first region and having a smallercross-sectional diameter than the first region. The method includes theact of providing a particle having a first size in which the particle isnot capable of passing from the first region into the second region. Theparticle is capable of reducing in size. The method also includes theact of delivering the particle having the first size to the first regionof the anatomical structure. The particle subsequently reduces from thefirst size to a smaller second size as the particle travels through theanatomical structure, allowing the particle to pass into the secondregion, and a therapeutic effect is achieved.

In some embodiments of the method, the particle includes a therapeuticsubstance that is released from the particle. In such embodiments, thetherapeutic effect results from the therapeutic substance.

In alternative embodiments, during the act of traveling through theanatomical structure and prior to the act of reducing to the secondsize, the particle reaches a diameter of the anatomical structurethrough which the particle cannot pass and at which the particle isconstrained for a transitory period until the particle reduces to thesecond size. In some such embodiments in which the anatomical structureis within a mammalian cardiovascular system, a brief period of reducedblood flow is caused during the transitory period. The therapeuticeffect is a therapeutic bodily response induced by the brief period ofreduced blood flow. In other such embodiments in which the particleincludes a therapeutic substance and in which the transitory period isless than one week, the therapeutic substance is released from theparticle. The resulting therapeutic effect is due to the therapeuticsubstance.

These and other aspects of the present invention may be betterappreciated in view of the detailed description and drawings of theexemplary embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an example of a heavily-branched network of blood vesselswithin the mammalian cardiovascular system;

FIG. 2 illustrates a particle capable of embolizing within a lumen for atransient period of time.

FIG. 3A illustrates an anatomical structure having a selected network oflumens in accordance with one embodiment of the present invention;

FIG. 3B illustrates an anatomical structure having a single lumen inaccordance with another embodiment of the present invention;

FIGS. 4A and 4B illustrate acts performed in accordance with one methodof delivering the composition to an anatomical structure;

FIGS. 5A and 5B illustrate acts performed in accordance with one methodof delivering the composition to a selected network of lumens;

FIGS. 6A and 6B illustrate acts performed in accordance with anothermethod of delivering the composition to a selected network of lumens.

FIGS. 7A, 7B, and 7C illustrate use of the composition to induce atherapeutic response in an anatomical structure having a selectednetwork of lumens in accordance with one embodiment of the presentinvention;

FIGS. 8A, 8B, and 8C illustrate use of the composition to induce atherapeutic response in an anatomical structure having a single lumen inaccordance with another embodiment of the present invention;

FIGS. 9A, 9B, and 9C illustrate use of the composition to induce atherapeutic response in an anatomical structure having a selectednetwork of lumens in accordance with another embodiment of the presentinvention;

FIGS. 10A, 10B, and 10C illustrate use of the composition to induce atherapeutic response in an anatomical structure having a single lumen inaccordance with another embodiment of the present invention.

DETAILED DESCRIPTION

The present invention discloses novel compositions and methods thatallow delivery of a therapeutic substance to a diseased region in themammalian anatomy without significant loss of the therapeutic substancecaused by the downstream flow of a fluid, such as blood. The inventionprovides compositions that are capable of treating multiple regions of aparticular lumen, or of a particular network of lumens, simultaneously.The compositions and methods have a therapeutic effect, via reduction inblood flow to a lumen or via sustained release of a therapeuticsubstance, in anatomical structures that may not have suitable diametersfor other techniques of treatment.

Composition of Matter

Referring to FIG. 2, a particle 28 is disclosed that is capable of beingdeposited in a passageway through which a substance, such as a bodyfluid, is transported. Particle 28 can embolize within a lumen for atransitory period of time to induce a therapeutic response. Thetherapeutic response can be induced, for example, by the reduction inflow of a substance, such as blood, through the passageway or by thesustained delivery of a therapeutic substance or a combination oftherapeutic substances.

Particle 28 can have any suitable initial size such that it is capableof being lodged within a region of a passageway upon delivery. Asuitable range for an initial diameter d of particle 28 is from about 5microns to about 100 microns. The actual diameter d depends on theprocedure for which particle 28 is used and the size of the lumen inwhich particle 28 is to be inserted.

Typically, the material from which particle 28 is made is most suitablya biocompatible, particularly hemocompatible, material that isnon-toxic, non-inflammatory, chemically inert, and substantiallynon-immunogenic in the amounts employed. Suitable materials from whichparticle 28 may be made include, but are not limited to, waxes andpolymeric materials. Examples of such waxes include partiallyhydrogenated vegetable oils, triglycerides, beeswax, saturated fattyacids, fatty acid esters, and phospholipids.

Suitable polymeric materials include, but are not limited to,bioabsorbable polymers, biomolecules, biodegradable inorganics, andbiostable polymers. A bioabsorbable polymer breaks down in the body andis not present sufficiently long after delivery to cause an adverselocal response. Bioabsorbable polymers are gradually absorbed oreliminated by the body by hydrolysis, metabolic process, bulk, orsurface erosion. Examples of bioabsorbable materials include, but arenot limited to, polycaprolactone (PCL), poly-D, L-lactic acid (DL-PLA),poly-L-lactic acid (L-PLA), poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),polyorthoesters, polyanhydrides, poly(glycolic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoesters, polyphosphoesterurethane, poly (amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), copoly(ether-esters), polyalkyleneoxalates, polyphosphazenes, polyiminocarbonates, and aliphaticpolycarbonates. Biomolecules such as dextran, hyaluronic acid,chondroitin sulfate, glycosaminoglycans, elastin, albumin, heparin,fibrin, fibrinogen, cellulose, starch, and collagen are typically alsosuitable. Examples of suitable biodegradable inorganics include, but arenot limited to, hydroxyapatite, dahlite, brushite, calcium sulphate,octacalcium phosphate, amorphous calcium phosphate, and beta-tricalciumphosphate. A biostable polymer does not break down in the body, and thusa biostable polymer is present in the body for a substantial amount oftime after delivery unless some modification is made to allow thepolymer to break down. Examples of biostable polymers include, but arenot limited to, Parylene®, Parylast®, polyurethane (for example,segmented polyurethanes such as Biospan®), polyethylene, polyethyleneteraphthalate, ethylene vinyl acetate, silicone, and polyethylene oxide.

In addition, particle 28 may be made of more than one material. In oneembodiment, particle 28 includes a mixture of at least two differentmaterials, each of which reduces in size in the lumen network ofanatomical structure 10 at a different rate. In another embodiment,particle 28 includes a first material and a second material that coversat least a portion of the first material. In such an embodiment, eachmaterial reduces in size in the lumen network of anatomical structure 10at a different rate.

In some embodiments, particle 28 contains a therapeutic substance thatis carried by the material of which particle 28 is made. The carriersubstance and the therapeutic substance within a single particle shouldbe mutually compatible, such that the characteristics, effectiveness,and physical structure of the therapeutic substance and the carriersubstance are not adversely altered. In addition, more than onetherapeutic substance may be contained in a single particle 28. Thenumber, type, and concentration of therapeutic substances withinparticle 28 are treatment-specific.

Therapeutic substances or agents may include, but are not limited to,antineoplastic, antimitotic, anti-inflammatory, antiplatelet,anticoagulant, anti fibrin, antithrombin, antiproliferative, antibiotic,antioxidant, antiallergic, antiangiogenic, angiogenic, and arteriogenicsubstances as well as combinations thereof. Examples of suchantineoplastics and/or antimitotics include paclitaxel (e.g., TAXOL® byBristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g., TAXOTERE®from Aventis S. A., Frankfurt, Germany) methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.,ADRIAMYCIN® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.,MUTAMYCIN® from Bristol-Myers Squibb Co., Stamford, Conn.) Examples ofsuch suitable anti-inflammatories include glucocorticoids such asdexamethasone, methylprednisolone, hydrocortisone and betamethasone,superpotent glucocorticoids such as clobestasol, halobetasol, anddiflucortolone, and non-steroidal anti-inflammatories such as aspirin,indomethacin and ibuprofen. Examples of such antiplatelets,anticoagulants, antifibrin, and antithrombins include sodium heparin,low molecular weight heparins, heparinoids, hirudin, argatroban,forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody,recombinant hirudin, and thrombin inhibitors such as ANGIOMAX™(bivalirudin, Biogen, Inc., Cambridge, Mass.) Examples of suchcytostatic or antiproliferative agents include actinomycin D as well asderivatives and analogs thereof (manufactured by Sigma-Aldrich,Milwaukee, Wis.; or COSMEGEN™ available from Merck & Co., Inc.,Whitehouse Station, N.J.), angiopeptin, angiotensin converting enzymeinhibitors such as captopril (e.g., CAPOTEN® and CAPOZIDE® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g., PRINIVIL® and PRINZIDE® from Merck & Co., Inc., WhitehouseStation, N.J.); calcium channel blockers (such as nifedipine),colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega3-fatty acid), histamine antagonists, lovastatin (an inhibitor ofHMG-CoA reductase, a cholesterol lowering drug, brand name MEVACOR® fromMerck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies(such as those specific for Platelet-Derived Growth Factor (PDGF)receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandininhibitors, suramin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. Anexample of an antiallergic agent is permirolast potassium. Examples ofantiangiogenic agents include thalidomide and angiostatin. Examples ofangiogenic agents include vascular endothelial cell growth factor (VEGF)and fibroblast growth factor (FGF). Examples of arteriogenic agentsinclude histimine, MCP-1, lipo-polysaccharide, and β-FGF. Othertherapeutic substances or agents that may be used includealpha-interferon, genetically engineered epithelial cells, anddexamethasone. While the preventative and treatment properties of theforegoing therapeutic substances or agents are well-known to thosehaving ordinary skill in the art, the substances or agents are providedby way of example and are not meant to be limiting. Other therapeuticsubstances are equally applicable for use with the disclosed methods andcompositions.

Preparation of Particles

Numerous methods are known to those having ordinary skill in the art forpreparing particles 28, with or without a therapeutic substance. Suchmethods include, but are not limited to, spray drying, supercriticalspray drying, emulsion techniques, grinding, and microencapsulation.

Spray drying is a versatile technique, as the primary requirement is theuse of a fairly volatile solvent. Suitable solvent volatilities rangefrom that of methylene chloride to that of water. In this particle 28preparation method, the material of which particle 28 is to be made isdissolved in a volatile solvent to form a solution. In embodiments inwhich particle 28 also contains a therapeutic substance, the therapeuticsubstance is suspended or co-dissolved in the solution. In suchembodiments, particular care should be taken to ensure that thetherapeutic substance is stable at the spray drying temperature and ableto withstand exposure to liquid-gas interfaces. The solution is thenspray-dried, a technique that is well known to one of ordinary skill inthe art. Any suitable spray drier may be used with any suitableparameters. Typical process parameters for a mini-spray-drier, such asBüchi™, include an inlet temperature of −24° C., an outlet temperatureof 13-15° C., a pump setting of 10 mL/minute, a spray flow of 600 N1/hr,and a nozzle diameter of 0.5 mm. The size of resulting particles 28 isdependent on the actual percent solids and spray drier parametersemployed.

Another method of particle 28 preparation is supercritical spray drying.Several variations of supercritical spray drying techniques are known.In one such variation, a solution containing a solvent and the materialof which particle 28 is to be made, with or without a therapeuticsubstance, is sprayed into a supercritical solvent, such as carbondioxide. The supercritical solvent effectively extracts the solvent usedto dissolve the material of which particle 28 will be made. Thistechnique may be carried out at a temperature as low as 32° C. Inanother variation of supercritical spray drying, the material of whichparticle 28 is to be made, with or without a therapeutic substance, isdissolved in the supercritical solvent. The resulting solution isspray-dried, and the supercritical solvent rapidly flashes off at roomtemperature to yield particles 28.

Particles 28 may also be prepared via a number of emulsion techniques.One such technique involves the preparation of an oil-in-water emulsion.The material of which particle 28 will be made, with or without atherapeutic substance, is dissolved in an organic solvent, usually withan emulsifier. The oil phase is dispersed into water usingultrasonication, mechanical agitation, or a microfluidizer. The organicsolvent is then removed by evaporation, and particles 28 are collectedand washed. The size of particles 28 is primarily dependent on thepercent solids of the oil phase, the shear rate, and stability of thedispersed phase. This technique also allows preparation of stableaqueous latexes of water insoluble particles 28.

Water-in-oil emulsions, which are known to those having ordinary skillin the art, tend to be less stable than the above-described oil-in-wateremulsions. However, a stable solution may be spray-dried to yieldparticles 28 in the form of microcapsules containing an aqueous phase.

A double emulsion technique, such as a water-in oil-in-water emulsion,is typically used to produce particles 28 in the form of microcapsulescontaining a therapeutic substance. The therapeutic substance isdissolved into the water phase and the material of which particle 28 ismade is dissolved into the oil phase. Emulsification is accomplished byadding the water phase to the oil phase. The solution is immediatelyadded to another aqueous phase with additional emulsification. Thesolvent is removed, typically by evaporation. The water may be left inthe capsule or removed by evaporation or lyophilization. Unlike theabove-described oil-in-water system, this water-in-oil-in-water systemallows particles 28 to be formed from water soluble materials.

Still other methods of making particles 28 include methods in which acarrier substance and a therapeutic substance are combined byconventional solvent-processing or melt-processing methods known tothose having ordinary skill in the art. Monolithic pieces are then castor fabricated, and fine particles 28 are made by grinding, milling orpulverizing such pieces. Particular care should be taken to control theprocessing temperature employed in embodiments in which the therapeuticsubstance is temperature-sensitive.

Particles 28 may also be prepared using microencapsulation techniques.Various methods for microencapsulation are known by persons havingordinary skill in the art, including methods of making variousmicroparticles having water-soluble compounds within them. A person ofordinary skill in the art will appreciate that a peptide may besubstituted with any rapidly swelling super-disintegrant. Theappropriate amount of such super-disintegrant may be from about 0.1% toabout 60%, or more particularly from about 10% to about 15%, by volumein the final microparticle.

Control of Particle Size Reduction Rate

Regardless of how particle 28 is made, particle 28 must ultimately becapable of size reduction. Not only must particle 28 be able to reducefrom a first size to a smaller second size, particle 28 should also becapable of doing so at a controlled rate such that particle 28 embolizeswithin the lumen for a transient period of time. For example, particle28 should embolize within the lumen long enough to induce a therapeuticeffect but not so long as to cause cell death in distal tissues.Further, in embodiments in which particle 28 contains a therapeuticsubstance, the transitory period of embolization preferably be less thanone week. Several mechanisms may be employed to control the rate atwhich particle 28 reduces in size and thereby control the amount of timefor which particle 28 will embolize within a lumen.

a. Rapid Hydrolysis

Hydrolysis is the mechanism by which many bioerodible polymers,including polyesters, polyanhydrides, and polyphosphazenes, erode. Mostsuch materials erode over a period of days to months and, as such, aretoo long-lived for use in accordance with some embodiments in thepresent disclosure.

Yet selection of particles 28 made from certain hydrophilicpolyanhydrides can yield particles 28 capable of the relatively rapiderosion rates suitable for use in the present technique. Of particularapplicability are those hydrophilic polyanhydrides based on hydrophilicdiacids. Such hydrophilic diacids include, but are not limited to,fumaric acid, maleic acid, succinic acid, and di-basic amino acids.

b. Controlled Dissolution

In some embodiments, a hydrophobic solid may be selected as the materialfrom which to make particle 28 to ensure a controlled dissolution rateof particle 28. Such hydrophobic solids include, but are not limited to,cholesterol, solid triglycerides, and hydrophobic proteins. Otherpotential compounds from which particle 28 may be made includesurfactants such as those from the SPAN®, TWEEN®, and PLURONIC® familyof surfactants. SPAN and TWEEN are registered trademarks of ICI AmericasInc. of Wilmington, Del. and PLURONIC is a trademark of BASF Corp. ofParsippany, N.J.

In some embodiments, it is desirable to make particle 28 of a highlysoluble material. Unaltered, such particles may dissolve too rapidly toembolize within a lumen at all. Others may dissolve too rapidly toembolize within a lumen long enough to effect a therapeutic response.Yet, the dissolution rate of such particles can be slowed to facilitatea suitable embolization period by techniques such as compression, mixingwith less soluble compounds, or preparation of systems with entangledpolymer chains.

Compression, which is often used in the pharmaceutical industry to makeoral dosage forms, may be utilized to control dissolution of particles28. A tablet press having cavities measuring 5-100 microns, may be usedto exert high pressure, e.g., several tons per square inch, upon thematerials of which particles 28 will be formed. This method ofcompression requires very small cavities, i.e., 5-100 microns, and evensmaller precursor materials. Alternatively, a relatively large tabletmay be formed by compression of materials from which particles 28 willbe made. The tablet may then be broken into smaller pieces that wouldretain the compressed properties. Particles 28 of suitable size may thenbe obtained by sieving or by use of a centrifugal separator.

In an alternative compression method, particles 28 of a size near to thedesired size are made using, for example, one of the above-describedtechniques. These particles 28 are blended with a compression material,such as a fatty acid or a wax. The compression material is soluble in asolvent in which the desired particles 28 are not soluble such as, forexample, an aliphatic solvent. The compression material should beimmiscible with particles 28. The blend of compression material andparticles 28 is compressed at high pressure to form a block. The desiredparticles 28, now isotropically compressed, can be recovered bydissolving away the surrounding compression material using the solvent.

The mixing of highly soluble compounds with less soluble compounds toform particles 28 having a desired dissolution rate is another method ofdissolution control. For example, the dissolution rate of microparticlesmade of galactose, a highly soluble compound, may be decreased by theaddition of a small amount of a hydrophobic substance to the galactose.Such microparticles are marketed as ECHOVIST® and LEVOVIST®. ECHOVIST isa registered trademark of Schering of Berlin, Germany, and LEVOVIST is aregistered trademark of Berlex Laboratories, Inc. of New Jersey. Theseparticles are used as echocontrast media and are approved forintravenous use. The hydrophobic compounds in such particles may bereplaced by hydrophobic therapeutic substances using methods known tothose having ordinary skill in the art.

The addition of hydrophobic counterions to a selected polyelectrolytepolymer is another strategy for controlling the dissolution of particles28 made thereof. The dissolution rate of water soluble heparin, forexample, can be slowed by the addition of hydrophobic counterions. Sucha complex is marketed under the tradename DURAFLO by EdwardsLifesciences Corporation of Irvine, Calif., a spin-off of BaxterInternational, Inc., of Deerfield, Ill. In addition, water solublepolymers such as carboxymethylcellulose and alginates can be made verywater insoluble by employing calcium, magnesium, or barium as acounterion.

Dissolution control can also be achieved by selecting a very highmolecular weight polymer, such as polyethylene oxide orpolyvinylpyrrolidone, from which to make particles 28. Although watersoluble, such materials dissolve slowly due to a high degree of polymerentanglement.

c. Neutralization

Certain polyelectrolytes are insoluble until neutralized. Polyacrylicacid as well as copolymers of acrylic acid with ethylene dissolveslowly, since such compounds are gradually neutralized followingintroduction to the bloodstream. The rate of neutralization, and thusthe rate of dissolution, can be controlled by varying the molecularweight and/or the composition of the copolymer or by using an alreadypartially neutralized polyelectrolyte in the preparation of particle 28.

d. Rapid Disintegration

As an alternative to complete dissolution, rapid disintegration ofparticles 28 into fragments that are small enough not to embolize avessel, i.e., less than 5 microns, can be used to facilitateembolization for a suitable transitory period. In addition, rapiddisintegration of particles 28 can be used to ensure that embolizationdoes not occur until the small fragments have traveled sufficientlydownstream from the location of delivery of particles 28. Suchdisintegration can be accomplished by incorporating very hygroscopicsubstances into particles 28. Examples of such disintegrants include,but are not limited to, croscarmellose and povidone, both of which areused as “super-disintegrants” in oral tablets. In addition, both ofthese compounds have been used in parenteral formulations. Disintegrantscan be incorporated in a single core, in multiple cores, or as acomplete dispersion in particle 28. Such methods of incorporation ofdisintegrants are well known by those having ordinary skill in the art.The disintegrant-containing particles 28 absorb large amounts of water,swell, and finally disintegrate.

Use of rapid disintegration as the method of limiting the time ofembolization, or alternatively as the method of controlling the locationat which embolization will occur, allows much flexibility in selectingthe material from which to make particles 28. As long as the fragmentsof particles 28 are small enough to prevent further embolization, oralternatively to sufficiently delay embolization, the material of whichparticles 28 are made can have a slower dissolution rate than would besuitable in the absence of such disintegrants within particles 28.

Control of Platelet Attachment and Coagulation

It will be apparent to those of ordinary skill in the art that plateletattachment and coagulation may result upon the embolization of particle28. In some instances, particle 28 may effectively clean itself byshedding proteins and platelets during dissolution. In other instances,the dissolution rate of particle 28 may be slowed by the barrier createdby such proteins and platelets. In addition, platelet attachment andcoagulation may lead to undesirable thrombosis of the embolized vessel.

One method of controlling platelet attachment and coagulation is toincorporate a material having anti-coagulant or anti-thrombogenicproperties into particle 28. By example and not limitation, 1-30% byweight heparin may be included in particle 28.

Another method of controlling platelet attachment and coagulation is toincorporate a material having anti-coagulant or anti-thrombogenicproperties into the infusion solution utilized to deliver particles 28to the treatment site. By example and not limitation, 10-100 USP unitsof heparin per milliliter of infusion solution may be employed.

Use of the Composition

Suitable Anatomical Structures

Particle 28 is capable of being delivered to anatomical structure 10.Anatomical structure 10 can be any portion of a network of lumens, or ofan individual lumen, capable of carrying a substance or a fluid in themammalian anatomy. The configuration of anatomical structure 10 is notlimited to the configuration illustrated by the Figures.

The number of lumens within anatomical structure 10 is not of criticalimportance. Anatomical structure 10 may be a lumen network having anynumber of lumens branching off in the downstream direction 12 into anynumber of other lumens, as depicted in FIG. 3A. In general, the lumenswithin a lumen network become progressively smaller in the downstreamdirection 12. The cross-sectional diameter of an individual lumen withinthe lumen network can be generally constant throughout. Typically,however, an individual lumen has a variable cross-sectional diameter.Regardless of the number of lumens within the lumen network and therelative sizes thereof, anatomical structure 10 in the form of a lumennetwork contains at least one region of smaller diameter locateddownstream from a region of larger diameter. The lumen network of FIG.3A includes a first region 30, a second region 32 located downstreamfrom first region 30, and a third region 34 located downstream fromsecond region 32.

Alternatively, anatomical structure 10 may include a single lumen, asdepicted in FIG. 3B. In such embodiments, the cross-sectional diameterof the lumen can be generally constant throughout the conduit so long asthe lumen contains at least one region of smaller diameter locateddownstream from a region of larger diameter. The lumen of FIG. 3Bincludes a first region 36, a second region 38 located downstream fromfirst region 36, and a third region 40 located downstream from secondregion 38.

Hereinafter, the term “first region” will be used to refer to the regionfurthest upstream and having the largest cross-sectional diameter, andthe term “second region” will be used to refer to the region downstreamof the first region and having a cross-sectional diameter smaller thanthat of the first region. In embodiments containing a third region, theterm “third region” will be used to refer to the region downstream ofthe second region and having a cross-sectional diameter smaller thanthat of the second region.

The term “region” is broadly defined to include a cross-sectional area,for example areas A, B, or C of FIG. 3A and areas D, E, or F of FIG. 3B,having any given thickness, for example, thickness t_(A), t_(B), ort_(C) of FIG. 3A and thickness t_(D), t_(E) or t_(F) of FIG. 3B. Thedistance between regions within anatomical structure 10 can be of anygiven length, for example length l_(AB) or l_(BC) in FIG. 3A and lengthl_(DE) or l_(EF) in FIG. 3B. Further, in embodiments in which anatomicalstructure 10 is a lumen network, such as that depicted in FIG. 3A,multiple regions may be located in the same lumen or in different lumenswithin the lumen network.

A particularly useful site of delivery of particle 28 is within thecardiovascular system of a mammalian subject. Thus, although the presentdisclosure is equally applicable to other anatomical structures 10within a mammalian subject, the following description and accompanyingFigures will detail the use of novel compositions and methods within themammalian cardiovascular system, and more particularly within themammalian arterial system.

Delivery of the Composition

Particle 28 is delivered to a predetermined site within anatomicalstructure 10. In general, particle 28 is delivered to the upstream,larger region within anatomical structure 10 having at least two regionsas defined above. More particularly, in embodiments where anatomicalstructure 10 is a lumen network, such as that depicted in FIG. 3A,particle 28 is delivered to first region 30. Similarly, in embodimentswhere anatomical structure 10 is a single lumen, such as that depictedin FIG. 3B, particle 28 is delivered to first region 36. In addition, inembodiments in which a lumen within anatomical structure 10 is partiallyor totally occluded, particle 28 should be delivered at a locationupstream of the occlusion.

The particular method of delivery of particle 28 is not of criticalimportance so long as the method chosen facilitates delivery to apredetermined site of anatomical structure 10 as described above. Onepossible method of delivery utilizes catheter 42 equipped with adelivery lumen 44 containing particle 28 as illustrated in FIG. 4A. Thismethod of delivery is suitable for use whether anatomical structure 10is a lumen network or a single lumen. Catheter 42 is advanced intoanatomical structure 10 until delivery lumen 44 is positioned at thelocation at which particle 28 is to be released. Once in position,particle 28 is released from delivery lumen 44 of catheter 42 intoanatomical structure 10, as depicted in FIG. 4B. In some embodiments,catheter 42 is attached to a programmable pump which may be worninternally or externally. In such embodiments, the pump is programmed todeliver pulses of particles 28 at a preselected interval ranging fromseveral hours to several days.

Yet another possible delivery method utilizes catheter 42 equipped witha single balloon 46 and a delivery lumen 44 containing particle 28 asillustrated in FIG. 5A. This method of delivery is suitable for use withembodiments in which anatomical structure 10 is a lumen network ratherthan a single lumen. Catheter 42 is advanced into anatomical structure10 until single balloon 46 is positioned downstream of the location atwhich second region 32 branches off from first region 30. Once inposition, single balloon 46 is inflated to cause an occlusion in firstregion 30. Particle 28 is released from delivery lumen 44 of catheter 42into first region 30 upstream of the location at which second region 32branches off from first region 30 as depicted in FIG. 5B.

FIGS. 6A-6B illustrate another possible method of delivery suitable foruse with embodiments in which anatomical structure 10 is a lumen networkrather than a single lumen. Catheter 42 equipped with a double balloon48 and a delivery lumen 44 containing particle 28, as illustrated inFIG. 6A. Catheter 42 is advanced into anatomical structure 10 untildouble balloon 48 is positioned to occlude the first region 30 atpositions both upstream and downstream of the location at which secondregion 32 branches from first region 30. Double balloon 48 is inflated,occluding the anatomical structure 10, and particle 28 is released fromdelivery lumen 44 of catheter 42 into first region 30 between theocclusions as depicted in FIG. 6B.

Journey of the Composition within the Selected Anatomical Structure

FIG. 7A depicts particle 28 upon delivery to first region 30 withinanatomical network 10 in the form of a lumen network. Particle 28 has afirst size too large to allow particle 28 to flow downstream from firstregion 30 to second region 32. Particle 28 is capable of size reductionsuch that particle 28 may reduce from its first size upon delivery tofirst region 30 to a smaller second size, allowing particle 28 to flowfrom first region 30 to the smaller second region 32 along path 50, asshown in FIG. 7B. In some embodiments, particle 28 must reduce from itssecond size to an even smaller third size to further flow along path 50from second region 32 to third region 34, as shown in FIG. 7C.

Similarly, FIGS. 8A-8C illustrate the journey of particle 28 along apath 52 within anatomical structure 10 in the form of a single lumen.Upon delivery to first region 36, as depicted in FIG. 8A, particle 28has a first size too large to allow particle 28 to flow downstream fromfirst region 36 to the smaller second region 38. Particle 28 is capableof size reduction such that particle 28 may reduce from its first sizeto a smaller second size, allowing particle 28 to flow from first region36 to second region 38 along path 52, as shown in FIG. 8B. In someembodiments, particle 28 must reduce from its second size to an evensmaller third size to further flow along path 52 from second region 38to third region 40, as shown in FIG. 8C.

FIGS. 9A-9C illustrate an alternative embodiment in which particle 28reduces in size by breaking into fragments 29 within anatomical network10 in the form of a lumen network. Upon delivery to first region 30, asshown in FIG. 9A, particle 28 has a first size too large to allowparticle 28 to flow downstream from first region 30 to second region 32.Particle 28 breaks into smaller fragments 29, allowing fragments 29 toflow from first region 30 to the smaller second region 32. Differencesin the diameter of the branching lumens can permit the smaller fragments29 to flow along path 50, as shown in FIG. 9B. In some embodiments,fragments 29 break into even smaller fragments 29 to further flow alongpath 50 from second region 32 to the smaller third region 34, as shownin FIG. 9C.

Similarly, FIGS. 10A-10C illustrate the route of particle 28 andfragments 29 thereof along a path 52 within anatomical structure 10 inthe form of a single lumen. As depicted in FIG. 10A, particle 28 has afirst size too large to allow particle 28 to flow downstream from firstregion 36 to second region 38 upon delivery to first region 36. In FIG.10B, particle 28 breaks into smaller fragments 29, allowing fragments 29to flow from the larger first region 36 to the smaller second region 38along path 52. In some embodiments, fragments 29 must break into evensmaller fragments 29 to further flow along path 52 flow from secondregion 38 to third region 40, as shown in FIG. 10C.

Therapeutic Effects Achieved Via Use of the Composition

In some embodiments, a therapeutic substance is released from particle28 or fragments 29 thereof. In some embodiments, a therapeutic substanceis released from particle 28 as particle 28 reduces in size and passesalong path 50 or path 52 within anatomical structure 10, as shown inFIG. 7A-7C or 8A-8C, respectively. Similarly, in embodiments in whichparticle 28 breaks into fragments 29, a therapeutic substance isreleased from fragments 29 as fragments 29 break into smaller fragments29, or otherwise reduce in size, and pass along path 50 or path 52, asshown in FIGS. 9A-9C and 10A-10C, respectively. In each of theabove-described embodiments, particle 28 or fragments 29 thereof reducein size at a rate such that particle 28 or fragments 29 do not embolizewithin anatomical structure 10 but rather flow unhindered throughanatomical structure 10. Such embodiments facilitate local delivery of atherapeutic substance within anatomical structure 10 for the treatmentof a patient.

In alternative embodiments, a therapeutic substance is released intoanatomical structure 10 by a temporarily stationary particle 28 or atleast one fragment 29 thereof. Upon reaching a lumen diameter throughwhich it cannot pass while traveling along path 50 or path 52 of FIG.7B-7C or 8B-8C, respectively, particle 28 will become constrained atthat location in anatomical structure 10, thus embolizing within thelumen. Similarly, upon reaching a lumen diameter through which it cannotpass while traveling along path 50 or path 52 of FIG. 9B-9C or 10B-10C,respectively, at least one fragment 29 of particle 28 will becomeconstrained at that location in anatomical structure 10, thus embolizingwithin the lumen. The therapeutic effect, however, is not achieved viacell damage or cell death, as embolization will continue only untilparticle 28 or fragment 29 sufficiently reduces in size to continueflowing through anatomical structure 10. Rather, the therapeutic effectis achieved via sustained release of the therapeutic substance fromparticle 28 or fragment 29.

The duration of the transitory period of embolization is typically lessthan one week. The exact duration will vary depending on the size of thevessel as well as on its location in the body. For example, a suitableembolization period for vessels within the brain is measured in seconds,and a suitable embolization period for vessels within the coronarysystem may be several minutes. The prolonged residence time of particle28 or fragment 29 at the location of embolization yields a prolongedresidence time of the released therapeutic substance at the location ofembolization as well. In addition, since blood flow is temporarilyhalted at the location of embolization, the therapeutic substance is notimmediately washed away from the vessel wall. Further, in someembodiments, the therapeutic substance may be released along path 50 orpath 52 before and/or after the transitory period of embolization inaddition to the above-described release of the therapeutic substanceduring the transitory period of embolization.

In still other embodiments, a therapeutic bodily response is not inducedby the release of a therapeutic substance from particle 28 nor fromfragments 29 thereof. Rather, particle 28 or fragments 29 effect atherapeutic bodily response within anatomical structure 10. Thetherapeutic bodily response, however, is not achieved via cell damage orcell death but via a transitory period of embolization while thetherapeutic substance is gradually released and applied according to therelative sizes of the fragments and lumens. Following the delivery ofparticle 28 having a first size to anatomical structure 10, particle 28travels along path 50 of FIGS. 7B-7C or path 52 of FIGS. 8B-8C untilreaching a lumen diameter through which particle 28 cannot pass.Particle 30 remains at that location in anatomical structure 10, thusembolizing within the vessel, until particle 28 sufficiently reducesfrom the first size to a smaller second size, thereby causing a briefperiod of reduced blood flow. Similarly, following the delivery ofparticle 28 having a first size to anatomical lumen 10, particle 28breaks into fragments 29 that travel along path 50 of FIGS. 9B-9C orpath 52 of FIGS. 10B-10C until reaching a lumen diameter through which aleast one fragment 29 cannot pass. Fragment 29 remains at that locationin anatomical structure 10, thus embolizing within the vessel, untilfragment 29 sufficiently breaks into smaller fragments 29, or otherwisereduces in size, thereby causing a brief period of reduced blood flow.Whether caused by the embolization of particle 28 or of fragment 29, theresulting brief period of reduced blood flow induces a therapeuticbodily response within anatomical structure 10.

In one such embodiment, pulsed delivery of particles 28, as describedabove, may induce brief periods of reduced blood flow and therebyfacilitate collateral growth. With each pulse, particle 28 will travelin the vasculature until reaching a diameter through which it cannotpass, thus embolizing the vessel and inducing local ischemia. Theembolization of the vessel is temporary in nature, as particle 28 willreduce in size. Several brief periods of reduced blood flow may triggera series of events leading to collateral growth in humans. Indeed,substantial collateral development has been induced in dogs afterseveral weeks in which eight two-minute blood flow restrictions werecaused every twenty-four hours. Although particle 28 may additionallyrelease a therapeutic substance to the region at which the vessel isembolized to induce collateral growth of vasculature, temporalmodulation of blood flow by embolization alone can effectively inducecollateral growth without application of the therapeutic substance.

EXAMPLES

Exemplary embodiments of the invention are illustrated below. Theseexamples are being given by way of illustration only and not by way oflimitation. The parameters given are exemplary, not limiting.

Example 1

A solution of lecithin and dexamethasone is made by dissolving 15 gramsof lecithine and 5 grams of dexamethasone in 100 ml of methylenechloride. A water-in-oil emulsion is prepared by stirring the solutionwith 250 ml of a solution of 0.5 perfluorotributylamine/PLURONIC® F-68in water with 1% (w/v) of heparin.

The emulsion is warmed to 40° C. to drive off the methylene chloride,forming microparticles. The microparticles are collected by filtrationand washed with near-freezing water. Particles are dried overnight undervacuum at 50° C.

The particles may be separated by size using standard particle sizingequipment such as a cyclone or tangential flow filtration, as are wellknown by those having ordinary skill in the art. A most suitable sizefraction has a range from about 10 microns to approximately 50 microns.Other particle sizes are possible.

Example 2

A solution of Basic Fibroblast Growth Factor (0.25 gram), heparin (1.0gram), and lactose (2.5 gram) in phosphate buffer pH 7.4 (100 ml) withHuman serum albumin (0.25 gram) is prepared, and emulsified in 250 ml ofmethylene chloride containing 1.75 grams of polylactide-co-glycolide.The resulting emulsion in quantity 100 ml is added to 500 ml water with0.5% perfluorotributylamine/pluronic F-68, and a double emulsion ofwater-in-oil-in water is prepared.

The methylene chloride is removed by warming the double emulsion to 40°C. for two hours. The particles are filtered off, washed with water,mixed with an aqueous solution of mannose in potassium phosphate buffer(20% mannose, w/v), and freeze-dried according to standard methods.

The particles may be separated by size using standard particle sizingequipment such as a cyclone or tangential flow filtration, as are wellknown by those having ordinary skill in the art. A most suitable sizefraction has a range from about 10 microns to approximately 50 microns.Other particle sizes are possible.

Example 3

A solution of plasmid DNA form gene construct (0.1 gram) and heparin (1gram) is prepared by stirring the plasmid and the heparin in a solutionof MW 100,000 dextran (5% w/v) and mannose (15% w/v) in water.

The solution is emulsified in 5.times. the volume cyclo-octane with 0.5%SPAN 80.

The solution is filled into standard lyophilization vials andfreeze-dried using standard industrial equipment and protocols.

The particles may be separated by size using standard particle sizingequipment such as a cyclone or tangential flow filtration, as are wellknown by those having ordinary skill in the art. A most suitable sizefraction has a range from about 10 microns to approximately 50 microns.Other particle sizes are possible.

For administration of the particles produced using the foregoingprocedures and other examples of procedures that would be known to onehaving ordinary skill in the art in combination with the disclosureherein, the particles are suspended in phosphate buffered saline with0.5% perfluorotributylamine/PLURONIC® F 68 and 10 IU units of heparinper ml. The suspension is suitably prepared immediately before use.

The particles can be locally infused using methods describedhereinbefore.

Particle sizes, polymer types, and drug types are selected based on thetreatment goal and intended procedure outcome. For example, if anangiogenic response in a particular set of vessels in the goal, then aDNA plasmid-promoting expression of VEGF is most suitable. The procedureoutcome is the growth of numerous small blood vessels in the treatedarea.

Fibroblast Growth Factor (FGF) containing particles can be used toinduce arteriogenesis, a process that enlarges existing small arteries.Particles are infused upstream of the treatment area, temporarilyembolizing the downstream target area, and releasing the drug beforedisintegrating. The outcome is to boost growth among smaller arteries.

Dexamethasone particles can be used to deliver a drug to an area underconditions that inflammation should be suppressed.

While particular embodiments of the present invention have been shownand described, it will be obvious to those having ordinary skill in theart that changes and modifications can be made without departing fromthis invention in its broader aspects. For example, the mammalianlymphatic system comprises a heavily-branched network of lymphaticvessels. Accordingly, the present invention may be utilized for thelocalized delivery of a therapeutic substance to a lumen network, or anindividual lumen, within the mammalian lymphatic system. Therefore, theappended claims are to encompass within their scope all such changes andmodifications as fall within the true spirit and scope of thisinvention.

We claim:
 1. A particle to form an embolus within a region of thecardiovascular system, comprising a biodegradable inorganic substanceselected from the group consisting of dahlite, brushite, calciumsulphate, octacalcium phosphate, amorphous calcium phosphate,beta-tricalcium phosphate and combinations thereof; wherein the formsthe embolus within the region for less than one week; and wherein adiameter of the particle is reduced or the particle disintegrates intofragments.
 2. The particle of claim 1, wherein the biodegradableinorganic substance is selected from the group consisting of dahlite,brushite, calcium sulphate, octacalcium phosphate, and combinationsthereof.
 3. The particle of claim 1, further comprising a therapeuticsub stance.
 4. The particle of claim 1, further comprising a polymericmaterial.
 5. The particle of claim 3, wherein the therapeutic substanceis selected from the group consisting of antineoplastic, antiplatelet,anticoagulant, fibrinolytic, antimitotic, thrombin inhibitor,anti-inflammatory, antiproliferative, antioxidant, antiangiogenic,angiogenic, arteriogenic and antiallergic substances, and combinationsthereof.
 6. A particle to form an embolus within a region of thecardiovascular system, the particle consisting essentially of: anoptional therapeutic substance; one or more optional materials; and abiodegradable inorganic substance selected from the group consisting ofdahlite, brushite, calcium sulphate, octacalcium phosphate, amorphouscalcium phosphate, beta-tricalcium phosphate, and combinations thereof;wherein the particle forms the embolus within the region for less thanone week; and wherein each of the one or more optional materials areindependently selected from the group consisting of polycaprolactone(PCL), poly-D, L-lactic acid (DL-PLA), poly-L-lactic acid (L-PLA),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxy-butyrate-co-valerate), polyorthoesters, polyanhydrides,poly(glycolic acid), poly(glycolic acid-co-trimethylene carbonate),polyphosphoesters, polyphosphoester urethane, poly (amino acids),cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate),copoly(ether-esters), polyalkylene oxalates, polyphosphazenes,polyiminocarbonates, aliphatic polycarbonates, dextran, hyaluronic acid,elastin, albumin, fibrin, fibrinogen, cellulose, starch, collagen,polyurethane, polyethylene, polyethylene teraphthalate, ethylene vinylacetate, silicone, polyethylene oxide, fumaric acid, maleic acid,succinic acid, di-basic amino acids, surfactants, fatty acids, waxes,polyvinylpyrrolidone, polyacrylic acid, croscarmellose, povidone,cholesterol, solid triglycerides, hydrophobic proteins, galactose,lecithin, lactose, and mannose.
 7. The particle of claim 6, wherein adiameter of the particle is reduced or the particle disintegrates intofragments.
 8. The particle of claim 6, where the therapeutic substanceis present.
 9. The particle of claim 8, wherein the therapeuticsubstance is selected from the group consisting of antineoplastic,antiplatelet, anticoagulant, fibrinolytic, antimitotic, thrombininhibitor, anti-inflammatory, antiproliferative, antioxidant,antiangiogenic, angiogenic, arteriogenic and antiallergic substances,and combinations thereof.
 10. The particle of claim 6, wherein one ormore materials are present.
 11. A particle to form an embolus within aregion of the circulatory system, comprising a biodegradable inorganicsubstance selected from the group consisting of dahlite, brushite,calcium sulphate, octacalcium phosphate, amorphous calcium phosphate andcombinations thereof; wherein the particle forms the embolus within theregion for less than one week.
 12. The particle of claim 11, wherein adiameter of the particle is reduced or the particle disintegrates intofragments.
 13. The particle of claim 11, further comprising atherapeutic sub stance.
 14. The particle of claim 13, wherein thetherapeutic substance is selected from the group consisting ofantineoplastic, antiplatelet, anticoagulant, fibrinolytic, antimitotic,thrombin inhibitor, anti-inflammatory, antiproliferative, antioxidant,antiangiogenic, angiogenic, arteriogenic and antiallergic substances,and combinations thereof.
 15. The particle of claim 11, furthercomprising a polymeric material.